|Many people label any problem that appears to be inherited a "genetic disease." However, though there are legitimate genetic diseases, there are also a variety of problems that have an inherited component but are of a fundamentally different nature. Dealing effectively with any genetic problem requires an understanding of the relationship between the genes (genotype) and the phenotype. In many cases this is lacking. In this article, I would like to describe some of the differences, in order to give breeders and owners a better understanding of what they are dealing with. Inborn Errors of Metabolism: The true "genetic diseases"|
The first clearly-described relationship between genotype and metabolic deficiencies is credited to Sir Archibald Garrod, an English physician. In 1901, he showed that the inherited disease alkaptonuria results from an inability to metabolize certain amino acids, leading to the accumulation of homogentisic acid. Some of this compound accumulates in skin and cartilage (the latter leading to arthritis). The rest is excreted in the urine, turning it black. Garrod suggested that the metabolic block was caused by an enzyme deficiency, though this was not confirmed until the enzyme (homogentisic acid oxidase) was characterized in 1958.
Since Garrod's time, many other inherited metabolic diseases have been discovered. Some can be managed by careful attention to diet; others cannot. A particularly nasty example is Tay-Sachs disease, which involves an enzyme important in lipid metabolism. Individuals homozygous for a deficiency in this enzyme accumulate a compound called a ganglioside in the nervous system. They appear normal at birth, but progressively lose motor function and die around three years of age. There is no treatment.
Most of these conditions involve mutations that lead to the production of a nonfunctional enzyme, or one that is totally absent. In heterozygotes, the single good copy of the gene is generally able to produce sufficient enzyme to handle the normal workload. However, in a few cases, carriers as well as affected individuals have to be careful about their diet or may exhibit less severe phenotypic effects.
Example of inherited metabolic diseases in dogs include phosphofructokinase deficiency in Cocker and Springer Spaniels, and pyruvate kinase deficiency in Basenjis.
Not all mutations involve metabolic pathways. Some involve proteins that have structural roles in cells and tissues. Others involve regulatory genes that control the correct sequence of events during development. These may lead to such problems as septal defects in the heart or the failure of the embryonic kidney to develop into the adult form. Nevertheless, all can legitimately be considered genetic diseases, as there is a direct one-to-one relationship between a single mutated gene and a particular problem. Conformational Diseases: The result of unnatural selection
Problems such as bloat (gastric dilatation-volvulus, or GDV) and hip dysplasia clearly have a genetic component, but also an environmental component and, perhaps, a behavioral one, as well (which also may be determined partially by the genes).
Bloat is not a "genetic disease" in the same sense as the metabolic and other disorders described above, and it seems unlikely that a single gene is responsible for bloat. One might better compare a bloat attack to a bad case of indigestion in a human. Some people are more prone to such attacks than others, and there may well be an inherited component, but other factors also come into play. Research into bloat suggests that diet, behavior, and conformation may all play a role.
Leaving aside the question of the role of genetics in behavior, the results suggest that the incidence of bloat increases with the size of the dog and the depth-to-width ratio of the chest cavity. This is a conformational problem, not a genetic disease. Certainly, the overall conformation is, ultimately, determined by the genes, but not by a single gene. There are probably dozens or hundreds of genes that go into determining the shape and size of the head, trunk, and limbs. Wherever there is genetic variability, one can select for larger, smaller, narrower, wider, etc. If the fancy as a whole decides that a taller, narrower dog looks more "refined," more of that description will be kept for breeding purposes, and the population will be shifted toward a more bloat-prone conformation.
When it comes to the question of correcting this problem, the solution, in theory, is simple. We stop breeding for a bloat-prone conformation and select for a slightly smaller dog with a chest cavity that is not so deep or narrow. Some may regard this as a retrogressive step, but we have to decide which we want to sacrifice.
I do not rule out the possibility that two dogs of identical conformation may have one or more genes that lead to one being more bloat-prone than the other. If we could identify these genes, we might be able to reduce the incidence of GDV somewhat while retaining some of the desired "refinement."
While it may be argued that there is nothing wrong with a tall, narrow dog aside from the greater risk for bloat, selecting for a conformation that is not functionally sound is a recipe for disaster. Wild canids do not move awkwardly. Any that did would be eliminated by natural selection. After thousands of years of evolution, the musculoskeletal system of the average wolf has found a combination that works efficiently. Because there is diversity in the gene pool, there is always the possibility of a chance combination of genes that produces an individual that can move more quickly and efficiently. There is also the possibility that a less efficient combination may arise, but it is not likely to be favored. In the artificial world of the show dog, one can insulate an individual from natural selection and favor a conformational extreme, because the breeder or the public thinks it looks more attractive or just different. Two such extreme dogs, bred together, may lead to something even more extreme and more popular. However, the changes in one component must be accompanied by changes in others, or the result, from a structural standpoint, may impose stresses that the components are not designed for. The result will be components easily damaged or deformed while the puppy is still growing. In such a case, one may not be dealing with genes that are "bad" and make a nonfunctional or defective product, just with a bad combination of genes. But if, during this "unnatural selection," the genes necessary to make a good combination have been discarded, where does this leave the breed?
|Breeders often talk about inbreeding and outcrossing as though they were the only possibilities -- and generally with negative comments about the latter. There are other possibilities, and I have long been a proponent of assortative mating. It is not a theoretical concept that doesn't work in practice; I know several breeders who do it and achieve good results. This essay will attempt to explain why it is a good idea, but first I need to define the alternatives. |
Though random mating is not a common breeding practice, understanding what this implies is important. Random mating is exactly what the name implies: mates are chosen with no regard for similarity or relatedness. (If the population is inbred to some extent, randomly-selected mates may be related.)
Random mating is one of the assumptions behind the Hardy-Weinberg formula, which allows one to calculate the frequency of heterozygous carriers from the frequency of individuals expressing some recessive trait in a population. Because inbreeding among purebred dogs and in other small populations decreases the frequency of heterozygotes, these estimates may be higher than the actual incidence.
Inbreeding and Linebreeding
Inbreeding is the practice of breeding two animals that are related (i.e., have one or more common ancestors). The degree of inbreeding may be assigned a value between 0 and 1, called the inbreeding coefficient, where 0 indicates that the animals have no common ancestors. Because the number of ancestors potentially doubles with every generation you go back in a pedigree, you eventually get to a point, even in a very large population, where there are simply not enough ancestors. Thus, all populations are inbred to some degree, and a true outcross (the term generally used when two animals are "unrelated") is not really possible. The term is generally misused to describe a cross between two animals with different phenotypes.
In a population with a limited number of founders, a maximum number of ancestors -- the effective population size -- is reached in some past generation. This number will be governed by various factors, such as the total population size, how far individuals travel during their lifetime, and whether there are inbreeding taboos or other mechanisms that reduce the likelihood of close relatives mating.
Inbreeding does not change allele frequencies directly, but it does increase the proportion of homozygotes. Individuals homozygous for deleterious genes are likely to be removed from the breeding pool by natural selection (if they do not survive to reproductive age) or by man.
Linebreeding is merely a term used for a particular type of inbreeding that often focusses on one ancestor who was considered exceptional. Particularly if it is a male, this exceptional ancestor may end up as grandfather and great-grandfather -- sometimes more than once -- in the same pedigree. Father-daughter, mother-son, and some other combinations also result in a disproportionate number of genes coming from a single ancestor. This type of close inbreeding is less common. [In contrast, the mating of full sibs or first cousins doubles up on two ancestors equally.]
As the result of several common practices, most pure-bred domestic animals are more inbred than they really need to be. One is that some breeders own a small number of animals and breed only within their own group. A second is that many breeders have the idea that outstanding animals can be produced by inbreeding -- by doubling up on the good alleles while somehow avoiding the bad. Even if you were to point out that this is a gamble, such breeders might respond that they are simply helping natural selection.
Beyond the conventional close-relative inbreeding, there is another practice that has much the same effect, namely the popular sire phenomenon (generally over-use of a well-promoted champion). In fact, many who breed to such a dog believe they are doing a "good thing," as they will be increasing the frequency of occurrence of the genes that made him a champion. What they may not realize is that they are increasing the frequency of all genes carried by this animal -- whether they are good, bad, or innocuous -- and that champions, like any other animal, carry a number of undesirable recessive alleles (the genetic load) that are masked by wild-type alleles. The result of the popular sire phenomenon is that almost all members of the breed will carry a little bit of Jake Hugelberg, and any undesirable trait carried by Jake will no longer be rare. Finding a safe, unrelated mate then becomes an exercise in futility.
If we lived in a world where all the genes followed the simple rule that there may only be good alleles, which are dominant, and bad alleles, which are recessive, then inbreeding could be an effective tool for improving a breed. However, during the past 25 years, geneticists have been directly measuring genetic diversity in populations by looking at the DNA or proteins, rather than at the phenotype. They have found that many individuals who cannot easily be distinguished by their phenotypic appearance nevertheless have considerable differences in their genotype. Some of these alternative alleles (termed neutral isoalleles) are functionally equivalent. Others have lost only a small portion of their normal function.
Suppose we have a "mutant" allele that has lost only 5-10% of its normal function. In many cases, this would not produce a noticeable effect. If you made an individual homozygous for this allele, you would not even be aware that you had done so. Now consider that the same fate may befall a number of genes during an inbreeding program. Eventually, you will have an individual that is considerably less fit than one carrying the normal alleles for all (or even most of) these genes. There is no magic formula for regaining what you have lost. You must start again.
[Sometimes mutant alleles result in an even more dramatic loss of function, but remain undiscovered under normal conditions. A good example is vWD in Dobermans.]
About the only animals that are routinely inbred to a high level are laboratory mice and rats. There, the breeders start breeding many lines simultaneously in the expectation that the majority will die out or will suffer significant inbreeding depression, which generally means that they are smaller, produce fewer offspring, are more susceptible to disease, and have a shorter average lifespan. Dogs are no different. If you can start with enough lines, a few may make it through the genetic bottleneck with acceptable fitness. However, dog breeders generally don't have the resources to start several dozen or more lines simultaneously.
Sometimes two different alleles may be better than one. Consider the major histocompatibility complex (MHC). These genes are responsible for distinguishing "self" from "foreign", and a heterozygous individual can recognize more possibilities than a homozygous one. Having a variety of MHC alleles is even more important to population survival. Not only does this provide better defense against pathogens, but there is growing evidence that parents who carry different MHC haplotypes may have fewer fertility problems. This is not a universally accepted theory, but today one is hard pressed to find a conservation or zoo biologist concerned with preserving an endangered species who would not list maintaining maximum genetic diversity as one of his/her primary goals.